Deep brain stimulation (DBS) improves debilitating symptoms of movement disorders when conventional medical therapies, cell transplant strategies, and the delivery of gene-delivered growth factors fail. Despite the remarkable efficacy of DBS, its therapeutic mechanism remains unclear. There is controversy regarding whether the therapeutic effects of DBS are associated with inhibition or excitation of target neurons, the introduction of new activity into the network, or a combination of these mechanisms. Additionally, it is unclear why stimulus frequency plays an important role in the clinical response to therapy. The fundamental hypothesis of this proposal is that unilateral subthalamic nucleus (STN) DBS in PD alters neuronal activity in the bilateral basal ganglia-thalamic-cortical motor system in a manner that is dependent on stimulation frequency. The following specific hypotheses will be tested in PD patients with unilateral STN DBS: (1) High frequency unilateral STN DBS in PD increases antidromic and orthodromic activation of contralateral STN neurons to a greater extent than low frequency stimulation. Preliminary findings of antidromic and orthodromic responses of STN neurons to contralateral DBS will be further explored using microelectrode recordings of STN neurons during contralateral high and low frequency STN DBS. Analyses will employ auto- and cross-correlograms and peristimulus rasters with histograms and Z-scores. (2) High frequency unilateral STN DBS in PD improves ipsilateral bradykinesia more than low frequency stimulation. Kinematic testing in the bilateral extremities of central and peripheral reaction time and movement time will be obtained at high and low stimulation frequencies during a wrist flexion/extension task and analyzed with ANOVA. (3) Unilateral STN DBS in PD alters activity in the ipsilateral premotor cortex. Magnetoencephalography (MEG) will measure the kinetics and localization of cortical magnetic fields evoked by high and low frequency STN DBS. Event detection, averaging, and peak detection will measure the kinetics of the evoked responses, and source localization will be calculated with single and two dipole models. As DBS is investigated for a wide variety of potential indications in neurology and psychiatry, there is a growing need to understand how it modulates brain activity to exert its clinical effects. Gaining such knowledge has the potential to improve the efficacy and safety of DBS in established indications and to guide future therapeutic innovations. PUBLIC HEALTH RELEVANCE: Deep brain stimulation (DBS) improves debilitating symptoms of movement disorders when conventional therapies fail. As DBS is investigated for a wide variety of potential indications in neurology and psychiatry, there is a growing need to understand how it modulates brain activity to exert its clinical effects. Gaining such knowledge has the potential to improve the efficacy and safety of DBS in established indications and to guide future therapeutic innovations.